Development of dual PLD1/2 and PLD2 selective inhibitors from a common 1,3,8-Triazaspiro[4.5]decane Core: discovery of Ml298 and Ml299 that decrease invasive migration in U87-MG glioblastoma cells.

O'Reilly MC, Scott SA, Brown KA, Oguin TH, Thomas PG, Daniels JS, Morrison R, Brown HA, Lindsley CW
J Med Chem. 2013 56 (6): 2695-9

PMID: 23445448 · PMCID: PMC3632306 · DOI:10.1021/jm301782e

An iterative parallel synthesis effort identified a PLD2 selective inhibitor, ML298 (PLD1 IC50 > 20000 nM, PLD2 IC50 = 355 nM) and a dual PLD1/2 inhibitor, ML299 (PLD1 IC50 = 6 nM, PLD2 IC50 = 20 nM). SAR studies revealed that a small structural change (incorporation of a methyl group) increased PLD1 activity within this classically PLD2-preferring core and that the effect was enantiospecific. Both probes decreased invasive migration in U87-MG glioblastoma cells.

MeSH Terms (10)

Benzamides Cell Line, Tumor Cell Movement Drug Discovery Enzyme Inhibitors Glioblastoma Humans Neoplasm Invasiveness Phospholipase D Spiro Compounds

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